The proposes studies are designed to test the hypothesis that changes in microvascular permeability of the cerebral circulation occur in response to physiological stimuli directed primarily at cerebral venules. Experiments that we have conducted suggest that cerebral venules, not arterioles and capillaries, are the primary sites of disruption of the blood-brain barrier during pathophysiologic condition, i.e., acute hypertension, hyperosmolar arabinose and stimulation with inflammatory mediators. In addition, disruption of the blood-brain barrier in venules during acute hypertension is associated with, and presumably related to, increases in cerebral venous pressure. The mechanism(s) by which increases in venous pressure disrupt the blood-brain barrier, however, are not clear. In the proposed studies, we will expand our original findings by examining possible cellular mechanism which may account for disruption of the blood-brain barrier in venules during cerebrovascular trauma. We will use a new technique, developed in our laboratory for studies of isolated cerebral venules in vivo, to examine the permeability characteristics of cerebral venules. Our first goal is to examine the relationship between changes in venular pressure and permeability of isolated cerebral venules. Our second goal is to examine possible second messengers involved in changes in venular permeability during increases in venular pressure, and during stimulation with mediators which are synthesized and released in the cerebral circulation during cerebrovascular trauma. Cerebral endothelium possess important peptidase enzyme systems which may function to modulate the severity of disruption of the blood-brain barrier during cerebrovascular trauma. We hypothesize that neutral endopeptidase and angiotensin-converting enzyme may play an important role in modulating the permeability of the cerebral microcirculation in venules during changes in venular pressure and during stimulation with important peptides that are synthesized and released by the cerebral circulation during cerebrovascular trauma. Thus, in the proposed studies, we will examine the role of neutral endopeptidase and angiotensin-converting enzyme in modulating the permeability of isolated cerebral venules in vivo. These two series of experiments will provide important and novel concepts with regards to cellular aspects which may function to control and/or modulate the permeability of cerebral venules during physiologic and pathophysiologic conditions.